Systematic review and meta-analysis of serum total testosterone and luteinizing hormone variations across hospitalized Covid-19 patients

A growing body of evidence suggests the role of male hypogonadism as a possible harbinger for poor clinical outcomes across hospitalized Covid-19 patients. Accordingly, we sought to investigate the impact of dysregulated hypothalamic-pituitary–gonadal axis on the severity of the clinical manifestations for hospitalized Covid-19 patients matched with healthy controls through a systematic review and meta-analysis. Databases were searched from inception to March 2022. A standardized mean difference (SMD) meta-analysis focused on hospitalized Covid-19 patients and healthy controls was developed for studies who reported total testosterone (TT) and luteinizing hormone (LH) levels at hospital admission. Overall, n = 18 series with n = 1575 patients between 2020 and 2022 were reviewed. A significant decrease in SMD of TT levels in Covid-19 patients compared to paired controls was observed (− 3.25 nmol/L, 95%CI − 0.57 and − 5.93). This reduction was even more consistent when matching severe Covid-19 patients with controls (− 5.04 nmol/L, 95%CI − 1.26 and − 8.82) but similar for Covid-19 survivors and non-survivors (− 3.04 nmol/L, 95%CI − 2.04 and − 4.05). No significant variation was observed for serum LH levels across studies. Patient related comorbidities, year of the pandemic, and total lymphocyte count were associated with the observed estimates. TT levels may be a useful serum marker of poor outcomes among Covid-19 patients. These findings may support the development of ad-hoc clinical trials in the Covid-19 risk-group classification and subsequent disease monitoring. The interplay between TT and immune response should be evaluated in future researches.


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Data items 10a List and define all outcomes for which data were sought.Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect.
Pag.12-13 10b List and define all other variables for which data were sought (e.g.participant and intervention characteristics, funding sources).Describe any assumptions made about any missing or unclear information. Pag.12-13

Study risk of bias assessment
11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process. Pag.13-14 Effect measures 12 Specify for each outcome the effect measure(s) (e.g.risk ratio, mean difference) used in the synthesis or presentation of results.Pag. 14

Synthesis methods
13a Describe the processes used to decide which studies were eligible for each synthesis (e.g.tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).
13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions. Pag.13-14 13c Describe any methods used to tabulate or visually display results of individual studies and syntheses.Pag.12-14 13d Describe any methods used to synthesize results and provide a rationale for the choice(s).If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used. Pag.13-14 13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g.subgroup analysis, meta-regression).Pag.14 13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results.Pag.13 Reporting bias 14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases). Pag.13

# Checklist item
Location where item is reported assessment Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome. Pag.13

Study selection 16a
Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram. Pag.4-5 16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.

Results of individual studies
19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g.confidence/credible interval), ideally using structured tables or plots.
Pag 5, table 1 Results of syntheses 20a For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies.
20b Present results of all statistical syntheses conducted.If meta-analysis was done, present for each the summary estimate and its precision (e.g.confidence/credible interval) and measures of statistical heterogeneity.If comparing groups, describe the direction of the effect.

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of all investigations of possible causes of heterogeneity among study results.Pag 5-7, supplementary files 20d Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results.Pag.6-7 Reporting biases 21 Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed.Pag 5-6 Certainty of evidence 22 Present assessments of certainty (or confidence) in the body of evidence for each outcome assessed.Pag.5-7 DISCUSSION Discussion 23a Provide a general interpretation of the results in the context of other evidence.Pag.7 23b Discuss any limitations of the evidence included in the review.Pag.10-11 23c Discuss any limitations of the review processes used.Pag.11 23d Discuss implications of the results for practice, policy, and future research.information for the review, including register name and registration number, or state that the review was not registered.Pag.1, 11 24b Indicate where the review protocol can be accessed, or state that a protocol was not prepared.Pag.11 24c Describe and explain any amendments to information provided at registration or in the protocol.Pag. 13 Support 25 Describe sources of financial or non-financial support for the review, and the role of the funders or sponsors in the review.Pag. 14 Competing interests